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Pathways of peritoneal tumour recurrence

after abdominal surgical trauma

ISBN 90-73235-49-9

2000 M.E.E. van Rossen

All rights reserved. No part of this thesis may be reproduced, stored in a retrieval

system of any nature, or transmitted in any form by any means, electronic, mechanical,

photocopying, recording or otherwise, included a complete or partial transcription,

without the permission of the author.

Printed by Optima Grafische Communicatie, Rotterdam, The Netherlands.

Pathways of peritoneal tumour recurrence

after abdominal surgical trauma



Ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam

op gezag van de Rector Magnificus Prof. dr. P.W.C. Akkermans MA

en volgens besluit van het College voor Promoties

De open bare verdediging zal plaatsvinden op woensdag 14 juni 2000 om 15.45 uur


Maria Elma Elizabeth van Rossen

geboren te Utrecht



Overige leden:


Prof. dr. J. Jeekel

Prof. dr. Th. van der Kwast

Prof. dr. SW.J. Lamberts

Prof. dr. H. Obertop

Dr. C.H.J. van Eijck

Dr. L.J. Hofland

The research was financially supported by the Department of Surgery/section

Oncological Surgery (7N) of the University Hospital Rotterdam Dijkzigt and the

Stichting Erasmus Heelkundig Kankeronderzoek.


Surgical treatment of malignancies within the abdominal cavity is regularly complicated

by peritoneal tumour recurrence. Peritoneal tumour recurrence refers to the

convalescence of tumour foci on the peritoneal membrane lining the abdominal cavity.

The underlying mechanisms of tumour recurrence are not fully clear. To elucidate this,

a profound understanding of the anatomy of the peritoneum and its elementary

response to surgical trauma is essential.

The flaring up of an inflammatory reaction followed by the initial steps of wound healing

are the first signs of regeneration after surgical trauma to the peritoneum. During these

processes, Pandora's box of cytokines and growth factors is opened with a potentially

ambiguous influence on tumour recurrence.

This thesis addresses the multi-factorial response of the peritoneum after surgical

injury, clarifying different pathways of stimulated tumour recurrence.


Part I


Part II

General introduction

General introduction

Aim of the thesis

Surgical peritoneal trauma and tumour recurrence in vivo



III Reduction of peritoneal trauma by using non surgical gauze leads to 37

less implantation metastasis of spilled tumour cells.


Adapted from: Annals of Surgery 1998; 227: 242-248

The inflammatory sequelae of surgery provoke enhanced tumour

recurrence; a crucial role for neutrophils and cytokines.

Submitted for publication

Part III Intra-abdominal blood loss and peritoneal tumour

recurrence in vivo

V Red blood cells inhibit tumour cell adhesion to the peritoneum.

Adapted from: British Journal of Surgery 1999; 86: 509-513



VI Scavenging of reactive oxygen species leads to diminished peritoneal 81

tumour recurrence.

Submitted for publication

Part IV Mesothelial and tumour cell adhesive interactions

in vitro

VII Effect of inflammatory cytokines and growth factors on tumour cell

adhesion to the peritoneum.

Accepted for publication (Journal of Pathology)



Part V


Identification of receptors on colon carcinoma cells binding extra

cellular matrix components.

Submitted for publication

Mesothelial and tumour cell growth in vitro

Paracrine interactions between mesothelial and colon carcinoma

cells in a rat model.

Adapted from: International Journal of Cancer 1997; 73: 885-890



X Paracrine modulators of peritoneal tumour recurrence in a rat model. 151

Submitted for publication

Part VI General discussion and Summary

XI Discussion and modes for clinical application

XII Summary and conclusions


List of publications

Samenvatting voor de leek


Curriculum vitae auctoris

List of abbreviations








To oma Una

Aan Giedo

General Introduction and

Aim of the Thesis

Part I

Chapter I


The peritoneum

The peritoneum is the largest and the most complex arranged serous membrane in the

body that lines both the intra-abdominal wall and the viscera contained within the

peritoneal cavity. It is capable of walling off infections and has several functions such

as the ability to synthesise, secrete or absorb. The peritoneum diminishes friction

among abdominal viscera, thereby enabling their free movement. 1-4 With a surface

area of some 10,000 cm2 in adults5, almost equal to that of the skin, this membrane

may be considered among the largest organs in humans. The peritoneal cavity

normally contains less than 100 ml of serous fluid that resembles an ultrafiltrate of

plasma and contains less than 3 g/dl protein.6 Taken together the surface area and the

functional capacity of the peritoneum, this enables the peritoneal cavity to be used for

continuous ambulatory dialysis (CAPO) as well as an internal reservoir during drainage

procedures (i.e. ventriculoperitoneal shunts).

The peritoneum and the serosal surfaces of organs within the peritoneal cavity are

composed of mesothelium and sub-mesothelial connective tissue. Highly differentiated

mesothelial cells, resting on a basement membrane, overly the connective tissue.

Embedded in this layer are numerous blood vessels and lymphatics. In terms of blood

supply per mass, the peritoneum is one of the most richly vascularised organs. 3 ;4;7

Interspersed among the connective tissue are poorly differentiated, epithelioid-like cells

similar to fibroblasts (figure 1.1 )4;8'10

Injury of the peritoneum triggers a series of events aimed at mesothelial regeneration.

Some of the prinCipal elements in the regenerative process are leukocyte influx into the

abdominal cavity, fibrin deposition and activation of both peritoneal macrophages and

the normally quiescent mesothelial cells. 3;7;11


>< ';:

~~ - ... (J) co .s=--" 0-Ola; (J) U E CO .0 .... ",-

en ~

Figure 1.1



Schematic representation of the peritoneum. 8M: basement membrane; PMN: leukocyte:

M~:macrophage; E: epithelioid cells; Call: collagen eo us fibers; V: vasculature.

Mesothelial cells

The mesothelium consists of a single layer of flattened cells with epithelioid

morphology. The mesothelial cells produce a lubricating suriactant that allows easy

gliding of opposing peritoneal suriaces. In addition, long microvilli project from the

apical surface of the cells to minimise the shear between facing peritoneal

surfaces. 8;9;12-16

Electron microscopic studies show that mesothelial cells are joined peripherally through

tight junctions while spot desmosomes provide mechanical stability.9;10;14;15

Nonetheless, the mesothelium is very susceptible to damage. Any form of injury

initiates acute changes of peritoneal morphology. Peritonitis is associated with a


transition in mesothelial morphology from flat to cuboidal, an increase in the

intercellular space and cell shedding.' Drying, wetting or rubbing causes mainly

denudation of the mesothelial surface. 15- 18

Minimal peritoneal tissue trauma already causes a reactive inflammatory response,

which coincides with the appearance of numerous leukocytes between and on

mesothelial cells. ' 9;20 Mesothelial cells are multipotential and capable of secreting pro-

and potentially anti-inflammatory mediators and are thus capable of contributing

significantly to a cytokine network operating to initiate, amplify and control peritoneal

inflammation (table 1.1).4,21,22

Cytokines Growth factors Miscellaneous Receptors

IL_1a23;24 TGF_~7,25-27 GM-CSF"" ICAM-I28-"

IL -1 ~23;24:31:34 bFGF"'oo RANTES" VCAM-I'"''

I L -6 7;24;31 ;37-39 PDGF-A" MCP_1",,",,7 I L -1 ~R24,34

IL_S7;11'''''o PDGF-B'o IL-1RA" TNF-aR37

TNF_a37 ;41 IGF_I42-44 PG ,,,,'0 EGF_R'o"o,


Table 1.1

Secretory products and receptors expressed by mesothelial cells.

Primary peritoneal defence mechanisms

Complement activation is an early component of the non-specific peritoneal defence

mechanisms and involves opsanisation of micro-organisms, enhancement of

inflammatory response, clearance of immune complexes and cell lysis,49 The normal

peritoneal cavity contains about 300 cellsimm3, including mainly macrophages plus

some lymphocytes and desquamated mesothelial cells